The purpose of this project is to elucidate the neural mechanisms and principles of treatment of chronic pain syndromes. Current intramural clinical drug trials are focused on antagonists of glutamate, the nervous system's primary excitatory neurotransmitter. Two subclasses of glutamate receptors, NMDA and AMPA/kainate receptors mediate neuroexcitation by opening ion channels, and their activation leads to increase in pain behaviors in animal models. In collaboration with Raymond Dionne, we completed the first human trial of any AMPA/kainate antagonist, showing that the experimental drug LY 293558 reduced pain caused by third molar extraction compared to a placebo. Topiramate, another drug that inhibits AMPA/kainate neurotransmission, reduced the frequency and intensity of trigeminal neuralgia compared to placebo in a pilot study. In another group of trials, we showed that chronic treatment with oral dextromethorphan, an NMDA receptor antagonist that we previously showed reduced diabetic neuropathy pain, was ineffective in patients with trigeminal neuralgia, anesthesia dolorosa, and atypical facial pain. Extramural collaborations include a collaboration with Johns Hopkins in which morphine treatment was superior to tricyclic antidepressant treatment in patients with postherpetic neuralgia, the first direct comparison of these two standard treatments. We have also initiated a program of studies of the genetic basis of chronic neuropathic pain. A collaboration with NIDCR's Scott Diehl and Ze'ev Seltzer of Hebrew University is pursuing the genetic factors that determine whether phantom limb pain occurs after amputation or sciatic nerve section in rodents and humans. A study of recombinant inbred mouse lines localized a gene affecting pain behaviors to a small region of one chromosome containing several genes whose gene products have previously been linked to pain processing.